CN1846696A - Method for producing enantiomer-free n-methyl-n- [(1s)-1-phenyl- 2-((3s)- 3-hydroxypyrrolidine- 1-yl)ethyl]- 2,2-diphenyl acetamide - Google Patents
Method for producing enantiomer-free n-methyl-n- [(1s)-1-phenyl- 2-((3s)- 3-hydroxypyrrolidine- 1-yl)ethyl]- 2,2-diphenyl acetamide Download PDFInfo
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Abstract
The invention relates to a new method for producing N-methyl-N- [(1S)- 1-phenyl-2- ((3S)-3- hydroxypyrrolidine- 1-yl)ethyl]- 2,2-diphenyl acetamide or N-methyl- N-[(1R)- 1-phenyl-2- ((3R)-3- hydroxypyrrolidine- 1-yl)ethyl]- 2,2-diphenyl acetamide and to the new compounds N-methyl- N-[(1S)- 1-phenyl- 2-((3S)- 3-hydroxypyrrolidine- 1-yl)- ethane] and N-methyl-N- [(1R)- 1-phenyl-2- ((3R)-3- hydroxypyrrolidine- 1-yl)- ethane] produced as intermediate products.
Description
The present invention relates to another kind of preparation N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2,2-diphenyl acetamide or N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2, the new method of 2-diphenyl acetamide and in the method as the N-methyl of intermediate-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethane] and N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxyl pyrrolidine-1-yl) ethane].
As (B.J.Pharmacol. (1994) as described in Barber etc., 133,1317-1327), compound N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2,2-diphenyl acetamide and its pharmaceutically useful salt have valuable pharmacological character, for example pain relieving, antiinflammatory and aquaretic effect, therefore, they are particularly useful for producing medicine.
Described in patent application DE19523502 or EP752246, it is found that this chemical compound is a compounds effective especially, it is applicable to the very medicine of particular form treatment inflammatory bowel.This chemical compound is that especially be suitable for and effective in this indication; because it alleviates pain that this disease has and simultaneously because inflammatory bowel is bringing under the ileac acute situations or the pain that produces, the motor response of normal again or setting in motion intestinal and do not have significant side effects.In addition, chemical compound can be used for the non-inflammatory intestinal diseases, for example IBS (zest intestinal condensation disease).
Patent application DE4034785A1 and DE4215213A1 or EP569802A1 have described by (2S)-2-N-carboxy ethyl-2-phenylglycine-N; N-[(3S)-3-hydroxyl tetramethyl amide and diphenyl acetyl group chlorine prepared in reaction N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2; the method of 2-diphenyl acetamide; described in DE4215213; initial compounds (2S)-2-N-carboxy ethyl-2-phenylglycine-N; N-[(3S)-3-hydroxyl tetramethylene amide; be also referred to as (1S)-[1-N-methylamino-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine) ethane can by make (1S)-1-amino-1-phenyl-2-ethyl chloride with (3S)-3-hydroxyl pyrrolidine reaction, subsequently with the methyl iodide preparation that methylates.Yet the problem of this preparation method is the dissolubility of initial product and after building-up process, the racemic product mixture by by-product contamination that obtains has to separate arduously.So far known preparation N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2, the method for 2-diphenyl acetamide is an effort and expensive, the yield that obtains based on initial compounds is low.
Therefore, the objective of the invention is to utilize a kind of preparation N-methyl of simple economy-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2,2-diphenyl acetamide method, maybe when using the enantiomer starting material, prepare N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2, the method of 2-diphenyl acetamide, it is mode and carrying out economically simply, it is by economy, easy dissolved starting material begins, obtain the product of enantiomer-pure as far as possible, so product can separate and purification with simple method.
Purpose of the present invention realizes by claim 1 method, previous unknown compound N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethane] as preparation N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2, the new intermediate of 2-diphenyl acetamide or N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxyl pyrrolidine-1-yl) ethane] as preparation N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2, the new intermediate of 2-diphenyl acetamide.
We find and can be prepared as follows formula (III) chemical compound with high yield and enantiopure form:
Wherein R and R
2Have following implication,
R is H, OR
1Or SR
1'
R
1Be A, aryl, heteroaryl, Si (R
3)
3Or COR
3'
R
2Be H, A, aryl, heteroaryl, Si (R
3)
3Or COR
3'
R
3Be H, A, aryl or heteroaryl,
A is the straight or branched alkyl that contains 1-6 carbon atom,
It comprises according to required end product amide coupling (3S)-3-hydroxyl pyrrolidine or the salt that forms as shown in the formula (3R)-3-hydroxyl pyrrolidine of (II) or they and hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid or suitable organic acid:
Wherein
R
2Be H, A, aryl, heteroaryl, Si (R
3)
3Or COR
3'
R
3Be H, A, aryl or heteroaryl,
With suitable (S) of the phenylglycine that replaces as shown in the formula the N-of (I)-or (R)-enantiomeric form:
Wherein
R is H, OR
1Or SR
1
R
1Be A, aryl, heteroaryl, Si (R
3)
3Or COR
3'
R
3Be H, A, aryl or heteroaryl,
M is H or the cation that is selected from alkali metal, alkaline-earth metal, ammonium or alkylammonium.
Alkyl contains 1-6, preferred 1,2,3 or 4 carbon atoms.Alkyl is methyl preferably, is ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group in addition, is amyl group, 1-in addition, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethyl propyl group.
The preferably unsubstituted phenyl of aryl or by halogen, OA or alkyl list or dibasic phenyl, in addition, for example xenyl or naphthyl.
Heteroaryl is for example furyl, thienyl, pyridine radicals, pyrrole radicals or thiazolyl preferably.
Si (R
3)
3Si (CH for example preferably
3)
3
COR
3Acetyl or benzoyl base for example preferably.
R is methoxy or ethoxy for example especially preferably.
R
1Especially for example methyl, ethyl, propyl group, butyl, phenyl, Si (CH
3)
3Or acetyl group.
R
2Especially for example H, the tert-butyl group, Si (CH
3)
3, acetyl group, benzyl or benzoyl, especially preferred H.
The amide of if desired, prepared formula (III) simply mode by removing N-methyl in formula (IV)-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethane] or N-methyl-N-[(1R)-1-phenyl-2-((3R)-3-hydroxyl pyrrolidine-1-yl) ethane] and in the blocking group reduction of hydroxyl of pyrrolidine transform.
React by activating carboxy acid with following formula V:
R wherein
4Be F, Cl, Br, I, OA or O-CO-A,
Can be by the salt that forms as shown in the formula the free alkali of the chemical compound of (IV) or itself and hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid or suitable organic acid:
Obtain enantiomeric compounds with pure form as shown in the formula (VI):
These chemical compounds preferably prepare as hydrochlorate, compound N-methyl-N-[(1S)-and 1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2,2-diphenyl acetamide is form known EMD61753; But can prepare similarly equally with the corresponding salt of above-mentioned acid.
Particularly, the N-methyl-N-[(1S)-and 1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2,2-diphenyl acetamide can be by the prepared in reaction of last and diphenyl acetyl group chlorine.
Usually can obtain by making the reaction of formula (I) chemical compound and formula (II) chemical compound as the synthetic formula of intermediate (IV) chemical compound, formula (I) chemical compound is preferred in this reaction, and wherein R has OR
1Define wherein R
1Be A, aryl, heteroaryl, Si (R
3)
3Or COR
2And R
2Be H, alkyl, aryl or assorted alkyl, have aforesaid preferred meaning.Unexpectedly, corresponding formylation compound is opposite with using, and obtains the enantiomer-pure product of formula (III).In the method, racemic fractionation can advantageously be saved.
Chemical compound (I) and reaction (II) can be carried out in any required aprotonic solvent.Especially suitable solvent is a polar aprotic solvent, and it is selected from ether, petroleum ether, acetone, Nitrobenzol, dimethyl formamide, dimethyl sulfoxide or other corresponding solvent.In this, starting material is dissolved in enough solvents, obtains 10-30% solution, and preferred reaction is carried out in as solvent at oxolane.
Chemical compound (I) and being reflected under 0-50 ℃ the appropraite condition of temperature (II) are carried out, yet especially good result is obtaining under normal pressure under 20-30 ℃ in room temperature.
For the activation starting material, need there be auxiliary reagent.These can be the adjuvant that also can be used as the peptide coupling reagent.Suitable compound is phosphorus Halides, phosgene, dicyclohexyl carbodiimide, the tributyl ammonium salt of pyridine, dichloro phosphoric acid phenylester, 2-chloro-1, phosphate ester, chloro sulfonyl isocyanate, the CH of for example phosphorus oxychloride, quantivalence III and V
3SO
2Cl-(C
2H
5)
3N, (C
6H
5)
3P-CCl
4-(C
2H
5)
3N, N, N '-carbonyl dimidazoles, N-(alkyl-carbonyl) imidazoles, anhydride or acyl chlorides, especially alkyl chloroformate, for example ethyl chloroformate.Other suitable auxiliary reagent is described in various handbook, for example C.Ferri " organic synthesis "; R.C.Larock " comprehensive organic synthesis; The introduction of functional group's preparation ", Verlag Chemie, 1989.
In addition, having alkali is needs.Suitable alkali is by reasoning in the above-mentioned handbook equally.This alkali is tertiary amine for example, and as triethylamine, yet inorganic base also can add, and suitable inorganic base is carbonate especially.When using alkali metal hydroxide, for example when sodium hydroxide or potassium hydroxide, especially should note adding accurately, because otherwise unwanted side reaction occurs.Yet,, can also adopt excessive hydroxyl pyrrolidine, thereby it is as alkali itself for simplifying processing.
The processing of the product that obtains (III) can be carried out with filtrate filtering out the post precipitation that obtains with common experimental chamber method.The solution that for example commonly used and suitable method comprises distilling off solvent, dissolves crude product again in organic solvent, obtain with water extraction for several times, distilling off solvent and by by suitable solvent, for example product that the recrystallization method recrystallization goes out to obtain in the methanol again.Yet, also can be other processing method well known by persons skilled in the art, for example additionally comprise the method for chromatography purification.
According to reaction condition, product (III) obtains as free alkali or with acid-addition salts that hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid or suitable organic acid form in aqueous solvent mixture, under one situation of back, separation can carried out according to after being separated of common experimental method.
Spendable suitable organic carboxyl acid is especially aliphatic, alicyclic, araliphatic, fragrance or heterocycle list or polybasic carboxylic acid, sulfonic acid or sulphuric acid, for example formic acid, acetic acid, propanoic acid, valeric acid, diethacetic acid, malonic acid, succinic acid, 1,5-pentanedicarboxylic acid., fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid .gamma.-pyridinecarboxylic acid, methane or ethane sulfonic acid, ethane disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, naphthalene-list-and disulfonic acid, lauryl sulfate.
Formula (III) chemical compound for example reduces in the presence of the hydride transfering reagent in nitrogen atmosphere in protective atmosphere.Suitable hydride transfering reagent is selected from metal alanates, preferred lithium aluminium hydride, metal alkoxide alanate, for example triethoxy lithium aluminium hydride, metallic boron hydrides, preferably NaBH
4Or borine, additionally having lewis acid is needs, for example boron trifluoride.
Reduction is preferably carried out in the aprotic, polar transmission with in to the hydride atent solvent.Suitable solvent is with above-mentioned identical, and especially suitable solvent is for example ether or oxolane.
For carrying out hydrogenation, formula (III) compound dissolution contains in the solution of hydride transfering reagent with equimolar amounts or excessive slightly adding down warm in suitable solvent.Yet, can also add the hydrogenant initial compounds of needs and the hydroborating reagent of appropriate amount with suitable manner, make in the reactant mixture that obtains initial compounds have based on the solvent concentration of 10-25% by weight.For finishing reaction, reactant mixture under refluxad stirred several hours.Reaction solution is subsequently according to method known to those skilled in the art processing, for example by adding by producing solvent mixture decomposing excessive hydride transfering reagent proton and aprotonic solvent and release reaction product.Suitable generation proton solvent for example is water or alcohols, as ethanol or methanol.Suitable aprotonic solvent is above-mentioned all polar aprotic solvents, especially oxolane, and the latter is preferred the use, because it obtains at the industrial anhydrous product that can be used as.
Product processing can be carried out after being separated according to the common experimental method.The crude product that obtains can be processed by method for crystallising, or in order to handle, it is dissolved in for example organic water immiscible solvent, uses excessive mineral acid, and the preferred salt acid treatment can be separated with crystal form subsequently by the salt that this method forms.
N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethane] or the further reaction of its dihydrochloride and suitable diphenyl acetic acid derivant (preferred acyl chlorides) obtain required end product N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2,2-diphenyl acetamide (formula VI, EMD 61753) is to carry out according to the method for describing in DE-A1-4034785 and DE-A1-4215213 or EP0569802A1.
Following embodiment is used to illustrate the present invention, but can not be used to limit the scope of the invention, because the different modification of embodiment are possible, produce required product N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethane] [formula (IV)], it can be used as preparation N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethyl]-2, the intermediate of 2-diphenyl acetamide.
Embodiment
Obtain (2S)-2-phenylglycine-N that the N-of formula III replaces by (2S)-phenylglycine of formula I, N-[(3S)-3-hydroxyl tetramethylene amide]
Embodiment 1
(2S)-N-formoxyl-2-phenylglycine-N, N-[(3S)-3-hydroxyl tetramethylene amide
By (2S)-N-formoxyl-2-phenylglycine (for example according to Huszthy, Peter; Oue, Masatoshi; Bradshaw, Jerald S.; Zhu, Cheng Y.; Wang, Tingmin etc., J.Org.Chem., EN, 57 (20) [1992] 5383-5394 are obtained by (S)-(+)-alpha-amido phenylacetic acid and acetic anhydride/formic acid)
(3S)-and the 3-hydroxyl pyrrolidine (according to Bhat, Krishna L.; Flanagan, DeniseM.; Joullie, Madeleine M., Synth.Commun., EN, 15 (7) [1985] 587-598 or Naylor, Alan; Judd, Duncan B.; Scopes, David I.C.Hayes, Ann G.; Birch, Philip J., J.Med.Chem., EN 37 (14) [1994] 2138-2144 are obtained by commercial (S)-1-benzyl-3-pyrrolidinol):
Will be in the 4.8ml ethyl chloroformate in the 10ml oxolane under agitation be added in 9g (2S)-N-formoxyl-2-phenylglycine and 5.5mlN-methyl morpholine among the 250mlTHF under-15 ℃ under nitrogen atmosphere; after 10 minutes, be added in 6.2g (3S)-3-hydroxy-pyrrolidine hydrochloride and 7ml triethylamine solution in the 50ml dimethyl formamide.After stirring 18 hours, isolate the precipitate that obtains, (the 2S)-N-formoxyl-2-phenylglycine-N that obtains, N-[(3S)-3-hydroxyl tetramethylene amide concentrates by separating in the filtrate by using the common experimental method, chromatogram purification subsequently.
1H-NMR：D
6-DMSO；3.0-3.8(m)，4.25(d)，5.0(s，br)，5.7(dd)，7.4(ArH)，8.0(ArH)，8.8(CHO)：
MS-FAB：(M+1)
+221，205；
Crystallization m.p.:97-101 ℃;
[α] D
20=+208 °, c=1 methanol.
Embodiment 2
(2S)-N-carboxyl benzyl-2-phenylglycine-N, N-[(3S)-3-hydroxyl tetramethylene amide
By (2S)-N-carboxyl benzyl-2-phenylglycine (for example according to Hones, RaymondCF; Turner, Ian; Howard, Kevin J., Tetrahedron Lett., 34 (39) [1993] 6329-9332 are obtained by (S)-(+)-alpha-amido phenylacetic acid and benzyl chloride carbonic ester)
(3S)-and the 3-hydroxyl pyrrolidine (according to Bhat, Krishna L.; Flanagan, DeniseM.; Joullie, Madeleine M., Synth.Commun., EN, 15 (7) [1985] 587-598 or Naylor, Alan; Judd, Duncan B.; Scopes, David I.C.Hayes, Ann G.; Birch, Philip J., J.Med.Chem., EN 37 (14) [1994] 2138-2144 are obtained by commercial (S)-1-benzyl-3-pyrrolidinol):
Under nitrogen atmosphere, will stir subsequently 30 minutes in the 14.3g in the 100ml oxolane (2S)-N-carboxyl benzyl-2-phenylglycine solution-treated with 5.5ml4-methyl morpholine and 4.8ml ethyl chloroformate and 10mlTHF under cooling.Add 4.36g (3S)-3-hydroxyl pyrrolidine and 10ml tetrahydrofuran solution subsequently, after stirring 18 hours, isolate the precipitate that obtains, (the 2S)-N-carboxyl benzyl-2-phenylglycine-N that obtains, N-[(3S)-3-hydroxyl tetramethylene amide is concentrated by separating in the filtrate by use common experimental method, be dissolved in the organic solvent,, concentrate once more and crystallization with the water washing.
1H-NMR：D
6-DMSO+TFA；5.1(s)，PhCH
2R；
FAB-MS：355(M+1)
+，311，196，176；
Denseness: oil;
[α] D
20=+108 °, c=1 methanol.
Embodiment 3
(2S)-N-carboxy ethyl-2-phenylglycine-N, N-[(3S)-3-hydroxyl tetramethylene amide
3.a)
By (2S)-N-carboxy ethyl-2-phenylglycine (for example according to Bodurow, C.C.; Boyer, B.D.; Brennan, J.; C.A.; Burks, J.E.; Deng TetrahedronLett., 30 (18) [1989] 2321-2324 are obtained by (S)-(+)-alpha-amido phenylacetic acid and ethyl chloride carbonic ester)
(3S)-and the 3-hydroxyl pyrrolidine (according to Bhat, Krishna L.; Flanagan, DeniseM.; Joullie, Madeleine M., Synth.Commun., EN, 15 (7) [1985] 587-598 or Naylor, Alan; Judd, Duncan B.; Scopes, David I.C.Hayes, Ann G.; Birch, Philip J., J.Med.Chem., EN 37 (14) [1994] 2138-2144 are obtained by commercial (S)-1-benzyl-3-pyrrolidinol):
Under nitrogen atmosphere,, stirred subsequently 60 minutes 16.7g (2S)-N-carboxy ethyl-2-phenylglycine solution-treated with 8.3ml 4-methyl morpholine and 7.1ml ethyl chloroformate and 20mlTHF under cooling.Add 6.5g (3S)-3-hydroxyl pyrrolidine and 30ml tetrahydrofuran solution subsequently, after stirring 18 hours, isolate the precipitate that obtains, (the 2S)-N-carboxy ethyl-2-phenylglycine-N that obtains, N-[(3S)-3-hydroxyl tetramethylene amide is concentrated by separating in the filtrate by use common experimental method, be dissolved in the organic solvent,, concentrate once more and crystallization with the water washing.
3.b)
By (2S)-N-carboxy ethyl-2-phenylglycine (referring to above) and (3S)-and 3-hydroxy-pyrrolidine hydrochloride (commercial available): in the 11g ethyl chloroformate that 24g (2S)-N-carboxy ethyl-2-phenylglycine and the mixture of 10g methyl morpholine in 100mlTHF is added under-10 ℃ approximately among the 100mlTHF.After stirring, add mixture and 10g methyl morpholine the mixture among 20mls of 12g (3S)-3-hydroxy-pyrrolidine hydrochloride in the 10ml deionized water.After stirring several hours, be separated, use the common experimental method, by concentrating, be dissolved in the organic solvent, with the water washing, concentrated and Crystallization Separation goes out (2S)-N-carboxy ethyl-2-phenylglycine-N again, N-[(3S)-3-hydroxyl tetramethylene amide.
Analytical data for modification 3a and 3b is as follows:
1H-NMR：D
6-DMSO；1.2(t)，3-3.8(m，br)，4.05(q)，4.25(s，br)，7.25-7.45(m)；
MS：293(M+1)
+，247，178，106；
Crystallization m.p.:124-126 ℃;
[α] D
20=+137 ℃=1, methanol.
The N-methyl of formula IV-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethane
Embodiment 4
The N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethane=
1-[(3S)-3-hydroxyl pyrrolidine-1-yl]-(2S)-2-methylamino-2-diphenylphosphino ethane
In nitrogen atmosphere that 2200ml 1.08mol lithium aluminium hydride-tetrahydrofuran solution is slowly warm, under agitation add 264g (2S)-N-carboxy ethyl-2-phenylglycine-N, N-[(3S)-3-hydroxyl tetramethylene amide] and the solution of 1400ml oxolane.After adding, mixture refluxed 3 hours, refrigerative reaction solution water/tetrahydrofuran compound hydrolysis.After sodium carbonate is handled and removed inorganic component, use the common experimental method by separated product in the filtrate.The oily crude product forms solid after by crystallization or chromatography purification.
1H-NMR：D
6-DMSO；2.1-3.1(m)，3.6(dd)，4.3(m)，7.15-7.35(m)；
MS：220(M
+)，205，120，100，91；
Outward appearance: according to batch crystalline yellow oil;
[α] D
20=+66.8 °; C=0.0938g is in 10ml methanol.
Embodiment 5
The N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl) ethane dihydrochloride=
1-[(3S)-3-hydroxyl pyrrolidine-1-yl]-(2S)-2-methylamino-2-diphenylphosphino ethane dihydrochloride
In nitrogen atmosphere that 2200ml 1.08mol lithium aluminium hydride-tetrahydrofuran solution is slowly warm, under agitation add 264g (2S)-N-carboxy ethyl-2-phenylglycine-N, N-[(3S)-3-hydroxyl tetramethylene amide] and the solution of 1400ml oxolane.After adding, mixture refluxed 3 hours, with postcooling, and reaction solution 80ml water/400ml tetrahydrofuran compound hydrolysis.After sodium carbonate is handled and removed inorganic component, use the common experimental method by separated product in the filtrate.The oily crude product is dissolved in organic, in the water immiscible solvent, handles with excessive hydrochloric acid.The fractional crystallization product is also dry.
1H-NMR：D
6-DMSO；3.4(m)，3.8(m)，4.2(m)，4.4(m)，4.9(m)，7.5?and?7.8(ArH)；
m.p.：240-242℃；
[α] D
20=-22.4 °; C=1 is in water.
Claims (2)
1, N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxyl pyrrolidine-1-yl)-ethyl]-2,2-diphenyl-acetamide is used for the treatment of application in the medicine of non-inflammatory intestinal diseases in preparation.
2, the described application of claim 1, wherein said non-inflammatory intestinal diseases is an irritable bowel syndrome.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19817393.8 | 1998-04-20 | ||
| DE19817393 | 1998-04-20 | ||
| DE19827633.8 | 1998-06-20 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998052469A Division CN1310884C (en) | 1998-04-20 | 1999-04-16 | Method for producing enantiomer-free N-methyl-N-[(1S)-1-phenyl-2-[(3S)-3-hydroxypyrrolidine-1-y1)ethyl]-2, 2-diphenyl acetamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1846696A true CN1846696A (en) | 2006-10-18 |
Family
ID=7865063
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100710951A Pending CN1846696A (en) | 1998-04-20 | 1999-04-16 | Method for producing enantiomer-free n-methyl-n- [(1s)-1-phenyl- 2-((3s)- 3-hydroxypyrrolidine- 1-yl)ethyl]- 2,2-diphenyl acetamide |
| CNB998052469A Expired - Fee Related CN1310884C (en) | 1998-04-20 | 1999-04-16 | Method for producing enantiomer-free N-methyl-N-[(1S)-1-phenyl-2-[(3S)-3-hydroxypyrrolidine-1-y1)ethyl]-2, 2-diphenyl acetamide |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998052469A Expired - Fee Related CN1310884C (en) | 1998-04-20 | 1999-04-16 | Method for producing enantiomer-free N-methyl-N-[(1S)-1-phenyl-2-[(3S)-3-hydroxypyrrolidine-1-y1)ethyl]-2, 2-diphenyl acetamide |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US6344566B1 (en) |
| EP (2) | EP1073634B1 (en) |
| JP (1) | JP4688292B2 (en) |
| KR (1) | KR100649175B1 (en) |
| CN (2) | CN1846696A (en) |
| AR (2) | AR019080A1 (en) |
| AT (2) | ATE527999T1 (en) |
| AU (2) | AU761721B2 (en) |
| BR (1) | BR9909731A (en) |
| CA (1) | CA2329210C (en) |
| CY (1) | CY1112314T1 (en) |
| CZ (1) | CZ301121B6 (en) |
| DE (2) | DE19827633A1 (en) |
| DK (2) | DK1073634T3 (en) |
| ES (2) | ES2251194T3 (en) |
| HK (1) | HK1039111A1 (en) |
| HU (1) | HUP0101600A3 (en) |
| MY (1) | MY120471A (en) |
| NO (1) | NO317984B1 (en) |
| PL (1) | PL206969B1 (en) |
| PT (1) | PT1607090E (en) |
| RU (1) | RU2298549C2 (en) |
| SI (2) | SI1607090T1 (en) |
| SK (2) | SK286442B6 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE10259245A1 (en) | 2002-12-17 | 2004-07-01 | Merck Patent Gmbh | Derivatives of asimadolin with covalently bound acids |
| JP2007509865A (en) * | 2003-10-30 | 2007-04-19 | ティオガ ファーマシュウティカルズ，インコーポレイテッド | Use of selective opiate receptor modulators in the treatment of neurological disorders |
| US20070160559A1 (en) * | 2006-01-12 | 2007-07-12 | Roszell James A | Skin disinfectant composition and methods for using |
| KR101263225B1 (en) * | 2007-03-30 | 2013-05-13 | 티오가 파마슈티칼스, 인코포레이티드 | Kappa-opiate agonists for the treatment of diarrhea-predominant and alternating irritable bowel syndrome |
| CN103664727A (en) * | 2013-12-19 | 2014-03-26 | 无锡万全医药技术有限公司 | Technology for preparing 1-[(3s)-3-hydroxypyrrolidine-1-base]-(2s)-2-methylamino-2-phenylethane with one-pot method |
| CN103772257A (en) * | 2013-12-31 | 2014-05-07 | 无锡万全医药技术有限公司 | Method for preparing 2-((3s)-3-hydroxy pyrrolidine-1-yl)-(1s)-1-phenethyl carbamate |
| EP3277274A4 (en) | 2015-04-01 | 2018-12-05 | Cedars-Sinai Medical Center | Anti-methanogenic lovastatin analogs or derivatives and uses thereof |
| CN112574068A (en) * | 2020-11-17 | 2021-03-30 | 万华化学（宁波）有限公司 | Preparation method of carbodiimide modified isocyanate with low color number and high stability |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4034785A1 (en) * | 1990-11-02 | 1992-05-07 | Merck Patent Gmbh | 1- (2-arylethyl) pyrrolidine |
| US5232978A (en) * | 1988-12-23 | 1993-08-03 | Merck Patent Gesellschaft Mit Beschrankter Haftung | 1-(2-arylethyl)-pyrrolidines |
| DE4215213A1 (en) * | 1992-05-09 | 1993-11-11 | Merck Patent Gmbh | Arylacetamide |
| DE4425071C2 (en) * | 1994-07-15 | 1996-08-29 | Degussa | Process for the production of optically active pyrrolidines with high enantiomeric purity |
| DE19523502A1 (en) * | 1995-06-28 | 1997-01-02 | Merck Patent Gmbh | Kappa opiate agonists for inflammatory bowel diseases |
| DE19531464A1 (en) * | 1995-08-26 | 1997-02-27 | Merck Patent Gmbh | N-methyl-N - [(1S -) - 1-phenyl-2 - ((3S) -3-hydroxypyrrolidin 1-yl -) - ethyl] -2,2-diphenyl-acetamide |
| US5968968A (en) * | 1996-07-24 | 1999-10-19 | Warner-Lambert Company | Diphenyl-cyclopropenes as selective K-agonists |
| DE19647538A1 (en) * | 1996-11-16 | 1998-05-20 | Merck Patent Gmbh | N-Substituted 2,2-di:phenyl-acetamide enantiomer preparation |
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